Defining the IBC Phenotype

• Published in: Oncology (Williston Park, N.Y.) Vol. 22; no. 14; p. 1566
• Main Authors: Zimmer, Alexandra S, Swain, Sandra M
• Format: Journal Article
• Language: English
• Published: Monmouth Junction Intellisphere, LLC 01.12.2008; MultiMedia Healthcare Inc
• Subjects: Cancer; Care and treatment; Chemotherapy; Diagnosis; Gene expression; Genetic aspects; Health aspects; Inflammatory breast cancer; United States
• ISSN: 0890-9091

Charafe-Jauffret et al defined IBC as "T4d tumors with no mandatory presence of dermal lymphatic emboli" in their analysis of 80 database IBC patients in a comparison with 552 consecutive non-IBC cases.[2] Expression of E-cadherin, EGFR, estrogen receptor (ER). MIB1/Ki67, HER2, MUC1, progesterone receptor (PR), and p53 was studied by immunohistochemistry and tissue microarray. Five markers were significantly associated with IBC in a multivariate analysis: E-cadherin, ER-negative status, MIBI, MUC1 cytoplasmic staining, and HER2 positivity (2+ or 3+). Most of these are not specific markers of IBC. In their analysis, however, the researchers found that a breast tumor with this full phenotype at diagnosis carried a 90.5% probability of an IBC diagnosis. One of these studied molecules, Ecadherin, has been repeatedly linked to IBC. Interestingly, E-cadherin has a controversial role, is generally thought to act as a tumor suppressor, and is expected to be absent in tumors associated with increased invasiveness and high metastatic potential. [3] Conversely, E-cadherin facilitates intercellular adhesion and enables the formation of cohesive tumor emboli as seen in IBC. [4] E-cadherin-positive staining was shown to be significantly different between cases of IBC (35.4%) and non-IBC (10.3%).[5] Although this protein was expressed in both IBC and non-IBC, in IBC tumors it was extensively present. Some genes involved in angiogenesis were upregulated in Bièche' s study, whereas others had similar expression levels in IBC and non-IBC. Confirming its angiogenic phenotype, IBC has been associated with increased microvessel density and endothelial cell proliferation in different analyses.[11,12] Van der Auwera et al[ 1 3] used real-time RT-PCR and found a significantly higher expression of VEGF-C and VEGF-D in IBC. Although VEGF-A expression was not altered, VEGFR2 was increased in IBC compared to non-IBC. Also studied in IBC is the c-MET proto-oncogene, which encodes for the high-affinity tyrosine kinase receptor for hepatocyte growth factor (HGF) or scatter factor. c-Met and HFG play a role in cell migration, morphogenic differentiation, organization of threedimensional tubular structures, cell growth, and angiogenesis. [23,24] Deregulation of c-Met and HGF has been shown to correlate with poor outcome in breast carcinoma. [25,26] c-Met protein immunohistochemical expression in 41 IBC tumors was compared with 480 non-IBC infiltrating ductal carcinomas. [5] c-Met was expressed in 100% of IBC cases but in only 64% of non-IBC cases. This study also found that phosphoinositide 3-kinase (PI3K) protein was concomitantly overexpressed with c-Met, supporting the hypothesis that c-Met activation in IBC induces downstream signaling through the PI3K pathway. c-Met is a potential therapeutic target for small molecules or biologic inhibitors of downstream signal transduction.